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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC. AND APOTEX CORP.
`Petitioners
`
`v.
`
`CELGENE CORPORATION
`Patent Owner
`_____________________
`
`Case IPR2018-00685
`Patent 8,741,929 B2
`Issued: June 3, 2014
`
`Title: METHODS OF USING 3-(4-AMINO-1-OXO-1,3-DIHYDRO-
`ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE
`FOR TREATMENT OF MANTLE CELL LYMPHOMAS
`
`
`
`_____________________
`
`PETITIONERS’ REQUEST FOR REHEARING
`
`Case No. IPR2018-00685
`_____________________
`
`
`
`
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`
`
`TABLE OF CONTENTS
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`
`
`I.
`
`INTRODUCTION ............................................................................................. 1
`
`II. LEGAL STANDARD ........................................................................................ 2
`
`III. ARGUMENT ..................................................................................................... 3
`
`A. The Board Erred in Denying Institution Pursuant to § 325(d),
`Overlooking or Disregarding that Drach Discloses Substantially
`More Than the References Substantively Before the Examiner ............... 3
`
`1. Unlike the References Substantively Considered By the
`Examiner, Drach Discloses the Clinical Use of Lenalidomide
`For Treating Cancers Similar to MCL ............................................ 4
`
`2. The Board Erred in Disregarding Its Own Finding that Drach
`Was “Stronger Evidence” than the References Before the
`Examiner ............................................................................................. 6
`
`B. The Board Misapprehended the Teachings of Querfeld in Finding that
`Querfeld Was Cumulative of Zeldis ............................................................. 7
`
`C. The Board Abused Its Discretion By Not Instituting a Trial, as
`Numerous Disputed Issues of Material Fact Exist Concerning
`Unexpected Results ........................................................................................ 8
`
`IV. CONCLUSION ................................................................................................12
`
`
`
`i
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`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) ............................................................................ 7
`
`Star Fruits S.N.C. v. United States,
`393 F.3d 1277 (Fed. Cir. 2005) ............................................................................ 3
`
`AGENCY PROCEEDINGS
`
`Merial Ltd. v. VIRBAC,
`IPR2014-01279, Paper No. 18 (Apr. 15, 2015) ................................................ 6, 7
`
`Yamaha Golf Car Co. v. Club Car, LLC,
`IPR2017-02141-2-3-4, 2018 WL 3198594 (Jun. 26, 2018) ........................... 3, 12
`
`STATUTES
`
`35 U.S.C. § 325(d) ............................................................................................passim
`
`CODE OF FEDERAL REGULATIONS
`
`37 C.F.R. § 42.71(c) ................................................................................................... 3
`
`37 C.F.R. § 42.71(d) .............................................................................................. 1, 2
`
`37 C.F.R. § 42.108(c) ........................................................................................... 9, 12
`
`
`
`
`
`
`
`
`
`
`
`Pursuant to 37 C.F.R. § 42.71(d), Apotex Inc. and Apotex Corp.
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`(“Petitioners”) submit this Request for Rehearing of the Board’s Decision Denying
`
`Institution of Inter Partes Review of U.S. Patent No. 8,741,929 (Paper No. 8)
`
`(“Decision”).
`
`I.
`
`INTRODUCTION
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`The Board should grant rehearing of its Decision not to institute based on
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`three crucial errors in its analysis.
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`First, with respect to Grounds 1 and 2, the Board overlooked or disregarded
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`that the Drach reference, a review article synthesizing relevant prior art for mantle
`
`cell lymphoma (“MCL”) treatment, discloses substantially more than what was
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`substantively considered by the Examiner. Specifically, the Board determined that
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`Drach, which discloses the clinical use of lenalidomide and was not substantively
`
`considered by the Examiner, was cumulative of references the Examiner
`
`considered that focused only on the use of thalidomide to treat MCL. The Board
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`also disregarded its own finding that Drach was “stronger evidence” than the
`
`thalidomide references because Drach disclosed that lenalidomide was “a new
`
`treatment paradigm” for MCL. Drach’s unique teachings were lynchpins of
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`Petitioners’ argument and the declaration of Petitioners’ expert, Dr. Thirman, with
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`respect to reasonable expectation of success and of lack unexpected results.
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`
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`
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`Second, with respect to Ground 2, the Board misapprehended that the
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`Querfeld reference, which was not considered during prosecution, was cumulative
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`of the Zeldis reference, despite Querfeld disclosing a Phase II lenalidomide clinical
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`study not disclosed by Zeldis. Querfeld’s additional teachings are relevant to the
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`issues of reasonable expectation of success and lack of unexpected results, and
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`were relied upon by Dr. Thirman and Petitioners.
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`Lastly, the Board should have instituted trial in light of numerous disputed
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`issues of material fact present here. Indeed, Dr. Thirman squarely disagreed with
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`the declaration of Dr. Zhang, which was submitted by Patent Owner during
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`prosecution, on the issue of unexpected results. Likewise, Dr. Thirman disagreed
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`with many factual assertions of Patent Owner in its Preliminary Response
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`regarding reasonable expectation of success and unexpected results. Such factual
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`disputes should have been viewed in a light most favorable to the Petitioner and
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`should ultimately be resolved at trial.
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`II.
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`LEGAL STANDARD
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`Requests for rehearing are governed by 37 C.F.R. § 42.71(d), which
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`provides in pertinent part that a party’s “request must specifically identify all
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`matters the party believes the Board misapprehended or overlooked, and the place
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`where each matter was previously addressed in a motion, an opposition, or a
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`reply.” Id. When rehearing a decision on petition, a panel reviews the decision for
`
`
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`2
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`
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`
`
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`an abuse of discretion. 37 C.F.R. § 42.71(c). An abuse of discretion occurs if the
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`Board’s original decision misinterprets the law, finds a fact not supported by
`
`substantial evidence, or makes “an unreasonable judgment in weighing relevant
`
`factors.” Yamaha Golf Car Co. v. Club Car, LLC, IPR2017-02141-2-3-4, 2018
`
`WL 3198594, at *1 (Jun. 26, 2018) (citing Star Fruits S.N.C. v. United States, 393
`
`F.3d 1277, 1281 (Fed. Cir. 2005)).
`
`III. ARGUMENT
`
`A. The Board Erred in Denying Institution Pursuant to § 325(d),
`Overlooking or Disregarding that Drach Discloses Substantially
`More Than the References Substantively Before the Examiner
`
`The Board denied institution of Ground 1 (Drach in view of Zeldis) and
`
`Ground 2 (Drach in view of Zeldis and Querfeld) on the basis of being cumulative
`
`of the combination of art that was before the Examiner (Zeldis in view of Damaj,
`
`Wilson and Kaufmann). Decision at 26 (citing 35 U.S.C. § 325(d)). With respect
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`to Drach specifically, the Board reasoned that Drach was substantially the same
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`prior art as Damaj, Wilson and Kaufmann and was “no more informative as to
`
`expected results” than those references. Decision at 23, 25-26. The Board erred in
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`making those determinations for two reasons: (1) it overlooked two key disclosures
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`in Drach regarding the clinical use of lenalidomide for cancers related to MCL and
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`(2) it disregarded its own finding that Drach was “stronger evidence” than
`
`
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`3
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`
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`references substantively considered by the Examiner and then inexplicably found
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`Drach cumulative anyway.
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`1.
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`Unlike the References Substantively Considered By the
`Examiner, Drach Discloses the Clinical Use of Lenalidomide
`For Treating Cancers Similar to MCL
`
`As an initial matter, the Board overlooked the fact that Drach provides key
`
`disclosures of the clinical use of lenalidomide for cancers similar to MCL that are
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`nowhere present in the publications before the Examiner. Unlike those
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`publications, Drach is a review article that synthesized many pieces of pertinent
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`prior art, including art relating to various clinical applications of lenalidomide.
`
`Drach provides two particularly relevant disclosures that are highly relevant to
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`both reasonable expectation of success and lack of unexpected results:
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` Lenalidomide was successful in treating multiple myeloma (a B-Cell
`
`cancer like MCL). Pet. 10, 16 and 19; Ex. 1002 ¶ 68.
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` Lenalidomide was the subject of various clinical trials including those
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`related to lymphoma (MCL is a lymphoma). Pet. 11, 16 and 19; Ex.
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`1002 ¶ 68.
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`By contrast, the publications before the Examiner make no reference to
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`lenalidomide whatsoever, much less the clinical application of that drug. That is
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`because those publications only disclose the clinical use of thalidomide for MCL.
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`And while the Board referenced Drach’s clinical application disclosures in its
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`Overview of the Asserted Prior Art, Decision at 11, it failed to address them in any
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`4
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`way whatsoever when conducting its analysis under § 325(d), even though those
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`disclosures were never considered by the Examiner. Decision at 22-26.
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`It is significant to note that in his declaration, Dr. Thirman relied heavily
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`upon those key disclosures with respect to reasonable expectation of success and
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`lack of unexpected results. For example, in his analysis that the claims at issue
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`would have been obvious based on Drach in view of Zeldis, Dr. Thirman cites to
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`Drach and states that “it was additionally known that lenalidomide was successful
`
`in treating MM [multiple myeloma] and was undergoing clinical trials for
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`lymphomas, both of which are relevant to MCL.” Ex. 1002 ¶ 68 (part of Section
`
`VII.A.a). Dr. Thirman further relied on this particular disclosure in support of his
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`opinion that alleged unexpected results during prosecution were entirely expected.
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`Ex. 1002 ¶ 109 (“The clinical results achieved by lenalidomide in relapsed,
`
`refractory or relapsed and refractory mantle cell lymphoma patients were not
`
`unexpected in light of the prior art at the relevant time, for the reasons discussed
`
`above in Section VII.A.a (which I incorporate here by reference).”).
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`Likewise, Petitioners made arguments related to reasonable expectation of
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`success and lack of unexpected results based on Drach’s disclosure of lenalidomide
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`use in MM treatment and clinical trials for lymphomas. Pet. at 10, 16, 19, 28-29.
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`For these reasons, the Board overlooked two of Drach’s key teachings in
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`finding that reference cumulative of Damaj, Wilson and Kaufmann, and the Board
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`5
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`
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`therefore abused its discretion in denying institution of Grounds 1 and 2 under
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`§ 325(d). Merial Ltd. v. VIRBAC, IPR2014-01279, Paper No. 18 at 8 (Apr. 15,
`
`2015) (recognizing that “misapprehend[ing] or overlook[ing] a significant fact
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`[establishes] the necessary abuse of discretion required by Rule 42.71(c)”).
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`2.
`
`The Board Erred in Disregarding Its Own Finding that
`Drach Was “Stronger Evidence” than the References
`Before the Examiner
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`Moreover, the Board erred in disregarding its own finding that Drach was
`
`not cumulative relative to the references before the Examiner. Drach discloses a
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`crucial teaching concerning the use lenalidomide to treat MCL, namely that
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`“thalidomide and its analogs (e.g., lenalidomide) are therefore important agents for
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`the new treatment paradigm of targeting both the tumor cell and its
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`microenvironment (mainly by interference with tumor-stromal interactions) [i.e.
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`MCL].” Ex. 1003 at 10.
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`Acknowledging this passage, the Board found that Drach suggested the use
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`of lenalidomide for MCL treatment and that “Drach – given its particular focus on
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`treating mantle cell lymphoma – is stronger evidence than Damaj, Wilson and
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`Kaufmann that one of ordinary skill in the art would have had a reason to treat
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`MCL patients with lenalidomide.” Decision at 25; see also id. at 23. Those
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`findings explicitly acknowledge that Drach discloses more than the references
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`
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`6
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`
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`substantively before the Examiner and therefore is not cumulative of them. And
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`again, Damaj, Wilson and Kaufmann do not even mention lenalidomide.
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`Not surprisingly, this key disclosure was relied upon by Petitioners and Dr.
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`Thirman in support of their arguments regarding reasonable expectation of success
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`and lack of unexpected results. Pet. at 18-19, 28-29; Ex. 1002 ¶¶ 68, 81-82, 109-
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`110.
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`In view of the foregoing, the Board plainly disregarded its own finding that
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`Drach is not cumulative of Damaj, Wilson and Kaufmann, and for this additional
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`reason it abused its discretion in denying institution of Grounds 1 and 2 under
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`§ 325(d). Merial, IPR2014-01279, Paper No. 18 at 8; cf. Belden Inc. v. Berk-Tek
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`LLC, 805 F.3d 1064, 1076 (Fed. Cir. 2015) (reversing Board’s conclusion of non-
`
`obviousness in IPR because Board disregarded its own finding regarding a
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`teaching of the prior art reference).
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`B.
`
`The Board Misapprehended the Teachings of Querfeld in Finding
`that Querfeld Was Cumulative of Zeldis
`
`The Board denied institution of Ground 2 (Drach in view of Zeldis and
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`Querfeld) in part based on its finding that Querfeld was cumulative of Zeldis.
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`Decision at 26 (citing 35 U.S.C. § 325(d)). But that finding misapprehended the
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`teachings of Querfeld. While both Zeldis and Querfeld disclose 25 mg of
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`lenalidomide daily for 21 days with 7 days rest in 28-day cycles (i.e. the same
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`dosage and regimens disclosed in Claims 4 and 20), Querfeld additionally
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`7
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`discloses the use of such dosing regimens in patients being treated for cutaneous T-
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`Cell lymphoma during a Phase II clinical trial. Decision at 11; Ex. 1004 ¶ 229;
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`Ex. 1005 at 2. This distinction is crucial, because the clinical application of
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`lenalidomide in a Phase II clinical study provides further evidence of reasonable
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`expectation of success for a POSITA that lenalidomide could be used in the
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`claimed dosages and regimens for treatment of MCL. This distinction also
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`undercuts allegations of unexpected results. Significantly, Querfeld was relied
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`upon by Petitioners and by Dr. Thirman for at least that purpose. Pet. 27-28; Ex.
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`1002 ¶¶ 105-107.
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`For these reasons, the Board misapprehended the teachings of Querfeld in
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`finding that reference cumulative of Zeldis, and the Board thus abused its
`
`discretion in denying institution of Ground 2 under § 325(d).
`
`C. The Board Abused Its Discretion By Not Instituting a Trial, as
`Numerous Disputed Issues of Material Fact Exist Concerning
`Unexpected Results
`
`Lastly, the Board abused its discretion in not instituting a trial given the
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`numerous disputed issues of material fact relating to the issue of unexpected results
`
`and the closely related issue of reasonable expectation of success. These disputed
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`factual issues arise in two contexts: (1) Dr. Thirman’s disagreement with the
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`Zhang declaration submitted by Patent Owner during prosecution and (2) Dr.
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`Thirman’s disagreement with Patent Owner’s positions set forth in its Preliminary
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`
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`8
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`
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`Response. At this early stage, those facts should have been viewed in a light most
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`favorable to the petitioner. 37 C.F.R. § 42.108(c). Instead, the Board did not
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`address these factual disputes and unfairly deprived Petitioners of a trial.
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`Turning first to the Zhang declaration, that declaration stated that MCL
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`patients treated with lenalidomide showed a 28% overall response rate. Ex. 1008
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`¶ 6. The Examiner concluded that this purported evidence of unexpected results
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`was sufficient to overcome the evidence of obviousness. Ex. 2007 at 81-82. Dr.
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`Thirman vigorously disagreed with the Zhang declaration. Ex. 1002 ¶¶ 108-110.
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`With minimal analysis, the Board dismissed Dr. Thirman’s declaration, finding
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`that nothing in Drach added anything over Damaj, Wilson, and Kaufmann with
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`respect to unexpected results, and determined that Dr. Thirman simply disagreed
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`with the Examiner’s view of the 28% response rate on the obviousness inquiry.
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`Decision at 25. Notably, the Board failed to meaningfully address many of the
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`factual issues that Dr. Thirman raised in response to the Zhang Declaration, Ex.
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`1002 ¶¶ 108-110, which are summarized in Paragraph 109 of his declaration:
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`109. The clinical results achieved by lenalidomide in relapsed, refractory, or
`
`relapsed and refractory mantle cell lymphoma patients were not unexpected
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`in light of the prior art at the relevant time, for the reasons discussed above
`
`in Section VII.A.a (which I incorporate here by reference). The prior art
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`teaches, at least, the following: (1) thalidomide was being used to treat
`
`relapsed and/or refractory MCL (Drach), (2) thalidomide had undesirable
`
`
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`9
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`
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`side effects (Drach), (3) lenalidomide was a less toxic, more potent,
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`structurally similar analogue of thalidomide being suggested for MCL
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`treatment (Drach and Zeldis), and (4) lenalidomide could be used for MCL
`
`treatment in the dosages, dosage forms and cycling regimen claimed by the
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`challenged claims of the ’929 patent (Zeldis, Querfeld, Celgene Press
`
`Release). See also supra Sections VI.A, VI.B, VII.A.
`
`
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`The Board abused its discretion in not viewing these factual issues in a light most
`
`favorable to petitioner, and any factual disputes arising therefrom should be
`
`addressed at trial.
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`At the same time, the Board apparently agreed with Patent Owner’s
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`arguments, unsupported by any expert declaration, on the issue of unexpected
`
`results.1 Focusing on what transpired during prosecution, the Board again failed to
`
`meaningfully addressing the factual issues raised by Dr. Thirman’s declaration,
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`which squarely opposed those raised by Patent Owner’s Preliminary Response.
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`The table below summarizes exemplary disputed facts relating to unexpected
`
`results/reasonable expectation of success:
`
`
`
`1 Unlike Petitioners’ arguments in its Petition, which were fully supported
`by Dr. Thirman’s expert declaration, Patent Owner submitted an essentially naked
`Preliminary Response, with only one portion of that submission relying on Zhang’s
`declaration presented during prosecution.
`
`10
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`
`
`Petitioner
`A POSITA would have reasonably
`
`Patent Owner
`A POSITA would not have reasonably
`
`expected lenalidomide to treat MCL
`
`expected that lenalidomide could
`
`based on what was known about
`
`effectively treat MCL based on
`
`thalidomide’s clinical use to treat MCL.
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`thalidomide because its use for MCL
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`See e.g. Pet. 18-19; Ex. 1002 ¶ 65.
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`was too limited. POPR 24-26.
`
`Structural similarity between
`
`“[M]ere structural similarity between
`
`thalidomide and lenalidomide would
`
`thalidomide and lenalidomide would not
`
`have provided a reasonable expectation
`
`have given a POSA any expectation that
`
`of success. Pet. 19; Ex. 1002 ¶¶ 65, 69.
`
`these two compounds would have
`
`substantially similar effects in any given
`
`patient population in vivo.” POPR 28.
`
`A POSITA would have reasonably
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`Areas of increased potency of
`
`expected lenalidomide to treat MCL,
`
`lenalidomide were not necessarily
`
`inter alia, based on its increased
`
`relevant to MCL. POPR 32.
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`potency over thalidomide. Pet. 20-21;
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`Ex. 1002 ¶¶ 71, 75, 76.
`
`A POSITA would have reasonably
`
`Because of the unique nature of MCL, a
`
`expected success in treating MCL based
`
`POSITA could not have expected that a
`
`on disclosure of lenalidomide’s use for
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`treatment option that worked for one
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`cancers related to MCL. Pet. 19-21; Ex.
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`disease state would work for MCL.
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`1002 ¶¶ 78, 88.
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`POPR 37.
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`
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`11
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`
`
`
`
`
`
`Petitioner
`Drach explicitly taught that
`
`Patent Owner
`Drach does not suggest, let alone
`
`lenalidomide was an important agent for
`
`disclose, that lenalidomide could be
`
`the new treatment paradigm of MCL at
`
`used to treat MCL. POPR 9.
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`the time, which would provide a
`
`POSITA a reasonable expectation of
`
`success. Pet. 18; Ex. 1002 ¶ 68.
`
`
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`Again, the Board abused its discretion in not viewing these factual issues in
`
`a light most favorable to Petitioner, and any factual disputes arising therefrom
`
`should be addressed at trial. Yamaha Golf Car Co. v. Club Car, LLC, IPR2017-
`
`02141-2-3-4, Paper 21, 2018 WL 3198594, at *2 (Jun. 26, 2018) (granting
`
`Petitioner’s request for rehearing because Board initially resolved disputed issue of
`
`material fact in favor of Patent Owner, contrary to 37 C.F.R. § 42.108(c)).
`
`In view of the foregoing, the Board abused its discretion in not instituting a
`
`trial given the numerous disputed issues of material fact relating to the issue of
`
`unexpected results and the closely related issue of reasonable expectation of
`
`success.
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`IV. CONCLUSION
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`In view of the foregoing, Petitioners respectfully request that the Board
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`reverse its denial of institution with respect to Grounds 1 and 2.
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`12
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`
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`Date: October 29, 2018
`
`
`
`
`
`
`By: /John Josef Molenda/
`
`John Josef Molenda
`Registration No. 47,804
`Steptoe & Johnson LLP
`1114 Avenue of the Americas
`New York, NY 10036
`Telephone: 212-506-3900
`Facsimile: 212-506-3950
`
`
`
`13
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`
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`CERTIFICATE OF SERVICE
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`
`
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`The undersigned hereby certifies that a copy of the foregoing
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`PETITIONERS’ REQUEST FOR REHEARING was served on October 29, 2018
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`by filing this document through the Patent Trial and Appeal Board End to End
`
`system as well as by delivering a copy via electronic email to the attorneys of
`
`record for the Patent Owner’s as follows:
`
`
`F. Dominic Cerrito
`nickcerrito@quinnemanuel.com
`
`Andrew S. Chalson
`andrewchalson@quinnemanuel.com
`
`Frank C. Calvosa
`frankcalvosa@quinnemanuel.com
`
`Daniel C. Wiesner
`danielwiesner@quinnemanuel.com
`
`
`
`
`J. Patrick Elsevier
`pelsevier@celgene.com
`
`Christopher J. Harnett
`charnett@jonesday.com
`
`Anthony M. Insogna
`aminsogna@jonesday.com
`
`
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`
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`Date: October 29, 2018
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`
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`
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`By: /John Josef Molenda/
`
`John Josef Molenda
`Registration No. 47,804
`Steptoe & Johnson LLP
`1114 Avenue of the Americas
`New York, NY 10036
`Telephone: 212-506-3900
`Facsimile: 212-506-3950
`
`Lead Counsel for Petitioners
`
`
`
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`
`
`